1. Field of the Invention
The present invention relates to a process for preparing 4-borono-L-phenylalanine (L-BPA), particularly to a process that is timesaving, efficient, cost effective and environmentally friendly.
2. Description of the Prior Arts
4-borono-L-phenylalanine (L-BPA) is an important boronated compound known to be useful for treatment of cancer through boron neutron capture therapy (BNCT). Therefore, many syntheses of L-BPA have been developed.
As shown in formula A, two synthesis approaches of L-BPA including formation (a) and formation (b) have been developed.

The approach demonstrated as formation (a) is by introduction of boronic acid group into phenylalanine, which is based on forming the C—B bond directly by the introduction of the dihydroxylboryl substituent to the phenylalanine fragment. J. Org. Chem. 1998, 63, 8019 discloses a process undergoing palladium-catalyzed cross-coupling between an amine-protected L-4-iodophenylalanine, such as (S)—N-Boc-4-iodophenylalanine, and a diboron compound, such as bis-(pinacolato)diboron. L-BPA is then obtained after removal of the protecting group of amine and boronic acid of the phenylalanine. However, an additional pre-process is further required for preparing the boronating agent, resulting in more time consumption and complicacy of the process, and thereby failing to prepare L-BPA in high yield. The prior art discloses that the carboxylic acid of (S)—N-Boc-4-iodophenylalanine reactant is protected into benzyl ester to improve the yield of the obtained protected L-BPA up to 88%. However, an additional step of removing the benzyl ester protecting group of the carboxylic acid of the protected L-BPA is further needed, which complicates the synthetic process. Accordingly, the drawbacks of this method also include the additional pre-process for preparing the boronating agent as mentioned above, and further include the time-consuming and multi-step synthesis involving the protection step of the carboxylic acid and the deprotection step of the carboxylic acid afterwards.
Another approach demonstrated as formation (b) involving coupling reaction between an amino acid and a boron-containing benzyl or benzaldehyde fragment is also developed. Biosci. Biotech. Biochem. 1996, 60, 683 discloses an enantioselective synthesis of L-BPA by coupling cyclic ethers of boronic acid and a chiral derivative from L-valine, wherein the cyclic ethers of boronic acid are prepared from 4-boronobenzylbromide in advance. However, the last synthetic step of the method readily results in undesired racemization of the amino acid. Thus, an enzymatic resolution step, which typically reduces the production yield, is required to obtain optically-pure L-BPA. Accordingly, the drawbacks of this method still include the additional pre-process for preparing the boronating agent, resulting in more time consumption and complicacy of the process, and thereby failing to prepare L-BPA in high yield.
Besides, 10B contained in L-BPA is known as the critical factor accumulated in tumor cells and subsequently irradiated with thermal neutron. Thus 10B renders L-BPA a treatment of cancer through boron neutron capture therapy (BNCT). However, natural boron exists as 19.9% of 10B isotope and 80.1% of 11B isotope. Therefore, many researchers have been developing synthetic processes suitable for producing L-BPA, and preferably suitable for producing 10B-enriched L-BPA.
As disclosed in J. Org. Chem. 1998, 63, 8019 mentioned above, the conventional methods comprise multi-step syntheses of the boronating agents, which reduce a large amount of 10B-enriched materials during the process. As a result, the methods are not suitable for producing 10B-enriched L-BPA.
As disclosed in Biosci. Biotech. Biochem. 1996, 60, 683 mentioned above, an optically pure L-BPA is not obtained until the enzymatic resolution step, and also the multi-step syntheses of the boronating agent render the transformations of the 10B-enriched materials during the process. Hence, the conventional method is not suitable for producing 10B-enriched L-BPA as well.
Furthermore, Bull. Chem. Soc. Jpn. 2000, 73, 231 discloses a method based on coupling 4-iodo-L-phenylalanine and pinacolborane in the presence of palladium catalyst. However, since the prior art is silent on how to produce 10B-enriched L-BPA and also 10B-enriched pinacolborane is not commercially available, the method is not suitable for producing 10B-enriched L-BPA, either.
In addition, Synlett. 1996, 167 discloses a method by coupling iodophenylborate and L-serine zinc derivatives. The method involves indispensable pre-preparation of the L-serine zinc derivatives and the pre-preparation of the iodophenylborate, thereby giving a low yield of L-BPA. Besides, the method is still not suitable for producing 10B-enriched L-BPA, for both 10B-enriched BI3 and 1,3-diphenylpropane-1,3-diol adopted in the method are not commercially available.
To overcome the shortcomings, the present invention provides a process for preparing L-BPA to mitigate or obviate the aforementioned problems.